The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) is very important in the etiology and treatment of numerous medical problems (R. A. Glennon, J. Med. Chem., 30, 1 [1987]). Many 5-HT receptors have already been identified and represent interesting objects for the selective handling of the serotoninergic function. The subtype 5-HT1A is especially interesting to the extent that compounds acting on this receptor may be used in the treatment of anxiety, depression, sleeping problems or cardiovascular problems (Brain 5-HT1A receptors: Behavioural and Neurochemical Pharmacology; Editors: C. T. Dourish, S. Ahlenius, P. H. Huston; Ellis Horwood, Ltd., Chichester [1987]). The 5-HT1A counteracting agents can likewise be used as anti-emetics (U. Wells, M. Ravenscroft, P. Bhandari, P. L. R. Andrews, Med. Sci. Symp., Ser. 5, 179 [1993]); F. Okada, Y. Torii, H. Saito, N. Matsuki, Jpn. J. Pharmacol., 64,109 [1994]), or as anti-secretion agents (J. S. Gidda, J. M. Schaus, EP 455,510 A2; D. C. Evans, J. S. Gidda, Gastroenterology, 104, A76 [1993]).
The present invention concerns new derivatives of phenoxyethylamine having a high affinity for the 5-HT1A receptors, procedures for their preparation, pharmaceutical compounds comprising them, and their use especially as secretion inhibitors for gastric acid or as anti-emetics.
Object of the invention are also products of general formula I: 
in which:
Ar represents a phenyl substituted by one or more substitutes;
R represents a hydrocarbonated radical containing 1 to 10 carbon atoms chosen from among the alkyl, alkenyl, linear or branched alkynyl radicals, cycloalkyl, cycloalkylalkyl or alkylcycloalkyl, monocyclic or polycyclic radicals, saturated or unsaturated;
the pyridyl or isoquinolyl radical;
a phenyl, which may be substituted by one or more substitutes, as well as the salts of these products.
Object of the invention is more especially products of general formula I such as defined above, characterized in that the substitute(s) which may carry the phenyl radical which represents Ar are chosen from among the halogen, lower alkyl, lower alkoxy, cyano, nitro, hydroxy, C(O)NR1R2, C(O)NHOR3, NHC(O)R4, NHC(O)NHR5, CH2NHC(O)NHR6, CH2OR, CH2NHC(O)R8, CO2R9, NHCO2R10, C(O)R11, [and] SR12 radicals;
in which R1, R2, R3, R4, R5, R6, R7, R8 are independently a hydrogen atom or a lower alkyl and R9, R10, R11, R12 are independently a lower alkyl;
and the substitute(s) which may bear the phenyl radical which may represent R are chosen from among the lower alkyl, lower alkoxy, halogen, hydroxy, nitro, amino or acylamino radicals.
In the definitions indicated above, the expression halogen represents an atom of fluorine, of chlorine, of bromine, or of iodine, preferably fluorine or iodine. The expression lower alkyl represents preferably an alkyl radical having 1 to 6 carbon atoms, linear or branched, and in particular an alkyl radical having 1 to 4 atoms of carbon such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, and tertiary butyl.
Among the alkenyl radicals, one may cite the vinyl, allyl, [and] butenyl radicals.
Among the alkynyl radicals, one may cite the ethynyl or propargyl radicals. Among the acylamino radicals, one may cite the acetylamino [and] propionylamino radicals.
The lower alkoxy radicals may correspond to the alkyl radicals indicated above. The methoxy, ethoxy, or isopropyloxy radicals are preferred.
The saturated monocyclic cycloalkyls may be chosen from among the radicals having 3 to 7 carbon atoms such as the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl radicals.
The mono- or polysaturated cycloalkyl radicals may be chosen from among the cyclobutene, cyclopentene, cyclohexene, cyclopentanediene, cyclohexadiene.
Examples of the polycyclic cycloalkyl radical are bicyclo-[2,2,1]-heptyl or adamantyl.
The products of formula I may form addition salts with the acids, especially pharmacologically acceptable acids.
Examples of salts are given below in the experimental part.
A particular object of the invention is general formula I compounds such as are described above, characterized in that Ar represents a phenyl radical substituted by a substitute chosen from among the hydroxy, methoxy, xe2x80x94C(O)NHMe, xe2x80x94NHC(O)Me, xe2x80x94NHCO2Rxe2x80x210, with Rxe2x80x210 representing a methyl or ethyl radical, xe2x80x94NHCONH2, xe2x80x94C(O)NHOH and R represents a cyclopentyl, cyclohexyl, cycloheptyl, cyclopentylmethyl, adamantyl, tertiary butyl, neopentyl, phenyl, [or] fluorophenyl radical.
The substitutes of the phenyl radical which may represent Ar are preferably situated in position 2 or 3.
More especially, the object of the invention are products described below in the examples, especially products responding to the following formulas:
N[4-{2-(2-methoxyphenoxy)ethyl}aminobutyl]benzamide;
N[4-{2-(2-methoxyphenoxy)ethyl}aminobutyl]adamantamide;
N[4-{2-(2-methylamino carbonyl phenoxy)ethyl]amino}butyl]benzamide;
N[4-{2-(2- hydroxyphenoxy)ethyl}aminobutyl]benzamide;
N[4-{2-(2- methoxyphenoxy)ethyl}aminobutyl]cyclohexylamide;
N[4-{2-(2- methoxyphenoxy)ethyl}aminobutyl]cycloheptylamide;
N[4-{2-(2- methoxyphenoxy)ethyl}aminobutyl]2-bicyclo[2,2,1]heptylamide;
as well as the salts of these compounds with organic or mineral acids.
The object of the invention is likewise a preparation procedure for general formula I products as defined above, characterized in that:
A) Either it is a formula II product: 
in which Ar has the meaning indicated above, with a product of formula III: 
in which X represents a halogen or a pseudo-halogen to obtain a product of formula IV: 
which formula IV product is subjected to a reaction for eliminating the phthalimide group to obtain a formula V product: 
which formula V product is treated by an acylation reagent derived from RCO2H acid in which R has the meaning indicated above to obtain a product of formula VI: 
B) or one causes a reaction of a product of formula VII: 
with N-benzylethanolamine of formula: 
to obtain a product of formula VIII: 
which is converted into a product of formula IX: 
in which Y represents a halogen or pseudo-halogen radical, a product of formula IX which is converted into a product of formula VI as previously defined, by causing a reaction of a phenol derivative of formula ArOH and formula VI products, which is converted into a product of formula I by splitting the benzyl function and formula I products which is converted, if desired, into acid salts by the action of the corresponding acid. 
In this reaction diagram, Ar and R are as defined above and X represents a starting group such as chloro, bromo, iodo, methanesulphonyloxy, benzenesulphonyloxy, or p-toluenesulphonyloxy, in other words, a halogen or pseudo halogen group.
The reaction of a compound of general formula II with a compound of general formula III to obtain a compound of general formula IV can be readily accomplished by heating in a polar solvent, for example, acetonitrile or dimethylformamide in the presence of an acid acceptor such as potassium carbonate or sodium carbonate. Phthalimides of general formula IV may be converted into primary amines of general formula V according to conventional methods, for example by heating with hydrazine hydrate, preferably in a solvent such as ethanol. The primary amines of general formula V thus obtained may be converted into amides of general formula VI by reaction with a derivative of the acid RCO2H which may be the appropriate acid chloride or the acid anhydride or other activated acid derivatives such as those generally used in peptide coupling reactions. The reaction is carried out in an inert solvent such as ether, tetrahydrofurane, or dichloromethane and generally in the presence of an acid acceptor such as a tertiary amine, for example, triethylamine or di-isopropylethylamine. 
In this reaction diagram Ar and R are as defined above and Y, identical to or different from X, represents a starting group such as chloro, bromo, iodo, methanesulphonyloxy, benzenesulphonyloxy, or p-toluenesulphonyloxy, in other words, a halogen or pseudo-halogen group.
Compounds of general formula VIII may be prepared by heating a compound of general formula VII with N-benzylethanolamine in a polar solvent such as an alcohol, in the presence of an acid acceptor such as a tertiary amine or an inorganic base such as sodium carbonate or potassium carbonate. Alternatively, compounds of general formula VIII can be readily prepared simply by heating a compound of general formula VII with an excess of N-benzylethanolamine in the absence of a solvent, preferably in a nitrogen atmosphere and to a temperature ranging between 60 degrees C. and 90 degrees C.
Compounds of general formula VIII thus obtained may be converted for example into chlorides of general formula IX (Y=Cl) by reaction with a chloride of methanesulphonyl in an inert solvent such as dichloromethane in the presence of an organic base such as triethylamine or di-isopropylethylamine. Compounds of general formula VI may be prepared from compounds of general formula IX by allowing the latter to react with a phenoxide anion produced from the appropriate ArOH phenol by using a base such as sodium hydroxide, potassium hydroxide, or sodium hydride. The reaction is carried out in an aprotic solvent and preferably in a dipolar aprotic solvent, for example dimethylformamide.
General formula I compounds are obtained by de-protecting the compounds of general formula VI according to known general methods for debenzylation, for example, catalytic hydrogenation or reaction with a choroformate such as vinyl chloroformate or xcex1-chloroethyl chloroformate followed by hydrolysis or methanolysis. Other methods of debenzylation such as described in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d (T. W. Green, P. G. M. Wuts; 2nd edition, J. Wiley and Sons, Inc., pp. 364-66 [1991]) may likewise be used to the extent that they are compatible with the substitutes with the aryl core(s) of the compounds of general formula VI.
Any salification of formula I products is likewise carried out according to the usual methods indicated below in the experimental part.
The compounds of the present invention have interesting pharmacological properties. It is thus that one has discovered that the compounds of the present invention have a high affinity for the 5HT1A receptor.
The compounds of the present invention may thus be used in various therapeutic applications.
The compounds may inhibit gastric acid secretion and induced vomiting, for example, by cis-platinum. Thus, the compounds of the invention may be used as anti-emetics or for the treatment of illnesses in which it is necessary or desirable to reduce gastric acid secretion, for example, gastric or duodenal ulcers, [or] gastritis, gastroesophagial reflux, gastric dyspepsia, Zollinger-Ellison""s syndrome, [or] nausea.
The compounds of the invention likewise exert an effect on gastric emptying and intestinal motility. For example, they may be used to fight against constipation, post-surgical atony, [or] gastroparesia.
They may likewise be used to fight against certain diseases of the nervous system such as anxiety, depression, sleep problems such as insomnia, dependence upon certain drugs, Alzheimer""s disease, eating disorders such as anorexia, [or] dizziness. The compounds of the invention may likewise be used to treat diseases of the cardiovascular system, especially hypertension.
There is below in the experimental part an illustration of the pharmacological properties of the compounds of the invention.
These properties make the formula I products suitable for a pharmaceutical use. The present application likewise has as its object, by way of medications, the formula I products as defined above as well as addition salts with pharmaceutically acceptable organic or mineral acids of said formula I products, as well as pharmaceutical compounds comprising as the active principle, at least one of the medications as defined above.
The invention concerns as well pharmaceutical compounds containing a compound of the invention or a pharmaceutically acceptable acid addition salt of the latter, in association with a pharmaceutically acceptable vehicle. The pharmaceutical compound may be in the form of a solid, for example powders, granules, tablets, gels, or suppositories. The appropriate solid vehicles may be for example calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinyl pyrrolidine, and wax.
Pharmaceutical compounds containing a compound of the invention may also be present in liquid form, for example, solutions emulsions, . . . suspensions or syrups. Appropriate liquid vehicles may be for example water, organic solvents such as glycerol or glycols as well as their mixtures in water in various proportions, added to oils or pharmaceutically acceptable fats. Sterile liquid compounds may be used for intramuscular, intraperitoneal, or subcutaneous injections, and sterile compounds may likewise be administered intravenously.
The invention likewise has as its object the use of formula I products as defined above for the preparation of antiemetic medications, medications intended to reduce gastric secretion, medications intended to accelerate gastric emptying, medications intended to accelerate the intestinal transit, medications intended to treat anxiety, depression, [or] sleep problems, as well as medications intended to treat cardiovascular diseases.
The invention likewise has as its object by way of new industrial products and especially by way of new industrial products intended for the preparation of formula I products, the products of formulas IV, V, VI, VIII, and IX as described above.
The starting products of the invention, especially the products of formulas II, III, and VII, are known products or those which may be prepared from known products. One may cite the following references: N-benzylethanolamine is a product marketed for example by the company ACROS.
The formula II products may be prepared by classical methods from the corresponding phenoxy ethyl amines, for example by the intermediary of benzamide followed by a reduction by lithium aluminum hydride or an equivalent method. Alternatively, one may use a reducing amination according to the usual methods.
Phenoxyethylethylamines may be prepared according to the usual methods, for example by reaction of a phenol with chloracetonitrile in a basic medium, [which] reaction [is] followed by the reduction of the nitrile by lithium aluminum hydride according to the method described in Chim. Ther. 8 (3) 259-270 (1973).
Formula III products are commercially [available] or may be manufactured by methods known to the person skilled in the art.
Thus it is that the product of formula III in which X represents a bromine atom is marketed by the company ACROS.
The products of formula III in which X represents another halogen atom such as chlorine or iodine or a pseudo-halogen such as the mesyl, tosyl, [or] phylsulfonyl radicals may be prepared by the usual methods from the corresponding alcohol marketed by the company Maybridge.
The products of formula VII may be prepared from omegaxe2x80x94hydroxybutyl amide according to known methods for the formation of a mesylate from an alcohol, for example according to the method described in J. Org. Chem. 35(9), 3195-6 (1970).